Dear Editors,
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can be life‐threatening. Anifrolumab is a type I interferon (IFN) receptor inhibiting IgG1κ monoclonal antibody administered intravenously every 4 weeks and indicated in the treatment of adults with moderate to severe SLE. 1 The type I IFN receptor is a key part of the body's defense against viruses, fungi, and bacteria. Its blockade dampens the immune response, making it harder for the body to fight off infections, and making infection a notable side effect of anifrolumab use. 2 , 3 , 4 We conducted a retrospective chart review of 144 patients seen at the Hospital of the University of Pennsylvania who received anifrolumab treatment between January 2021 and October 2024, and identified 14 patients who experienced an atypical infection, three of which were severe.
Of the 14 patients identified, all were female, with a median age of 42.5 years. The time from anifrolumab initiation to adverse reaction ranged from 1 week to 20 months, with a median of 7 months. Upper respiratory infection (URI), bronchitis, and herpes zoster, which occurred in eight of the cases, are commonly known infections associated with anifrolumab use (Table 1). 3 , 4 Here, we highlight three cases with atypical adverse reactions.
TABLE 1.
Patient Demographics.
| Patient Number | Diagnosis | Sex, Age (y) | Adverse Reaction | Time from Initiation (months) | Concomitant Medications |
|---|---|---|---|---|---|
| 1 | SLE, DLE | F, 22 | Hand HSV‐2 | 20 | Hydroxychloroquine, azathioprine, MMF |
| 2 | SLE, DLE | F, 26 | Lymphadenitis | 8 | Hydroxychloroquine |
| 3 | SLE/DM overlap syndrome | F, 54 | Severe URI, Fungal esophageal infection, oral staph infection | 0.25, 2, 4 | Azathioprine, MTX, prednisone (8 mg) |
| 4 | SLE | F, 45 | Severe tinea corporis infection | 0.75 | Hydroxychloroquine, MMF |
| 5 | SLE, DLE | F, 28 | Psoas, paracolic, & perihepatic abscesses | 5 | Hydroxychloroquine |
| 6 | SLE | F, 36 | Multifocal PNA & sepsis | 3 | Hydroxychloroquine, belimumab |
| 7 | SLE | F, 46 | URI | 13 | MMF |
| 8 | SLE/DLE/Tumid LE | F, 49 | Bronchitis | 2 | Hydroxychloroquine, MMF, quinacrine |
| 9 | SLE/Sjogren overlap syndrome | F, 74 | Bronchitis | 3 | Hydroxychloroquine |
| 10 | SLE | F, 52 | Bronchitis | 13 | Hydroxychloroquine, azathioprine |
| 11 | SLE | F, 33 | Bronchitis | 10 | Prednisone (10 mg) |
| 12 | SLE | F, 41 | Bronchitis | 13 | Hydroxychloroquine |
| 13 | SLE | F, 44 | Herpes zoster | 11 | Methylprednisolone (4 mg) |
| 14 | SLE/DLE/Tumid LE | F, 37 | Herpes zoster | 1 | Methotrexate, MMF, prednisone (8 mg) |
Abbr.: SLE, systemic lupus erythematosus; DLE, discoid lupus erythematosus; DM, dermatomyositis; Tumid LE, tumid lupus erythematosus; URI, upper respiratory infection; PNA, pneumonia; HSV‐2, herpes simplex virus 2; MMF, mycophenolate mofetil; MTX, methotrexate.
Bolded patients are those specifically highlighted in this case series.
Patient 1 is a 22‐year‐old female with a history of SLE and discoid lupus erythematosus (DLE). She was taking 100 mg azathioprine daily for 3 years and mycophenolate mofetil (MMF) 2,000 mg daily for 2 years prior to anifrolumab initiation. Fourteen months after initiating monthly infusions of anifrolumab 300 mg, she developed tender, non‐inflammatory bullae on the right palm, right arm, abdomen, legs, and inner lip (Figure 1). On presentation to our dermatology clinic, she had two bullae proximal to her right palm. Fluid from the bulla on the arm was aspirated and herpes simplex virus 2 (HSV‐2) was detected via PCR analysis, after which the patient was started on valacyclovir 3 g daily for 14 days followed by prophylaxis with 1 g daily to prevent recurrence.
FIGURE 1.
(a, b) Progression of HSV‐2 on the palmar aspect of the right hand in Patient 1. (c) CT image showing a psoas abscess in Patient 5. (d–f) Widespread dermatophytosis in Patient 4, with the punch biopsy site shown in (d).
Patient 4 is a 45‐year‐old female with a history of SLE. She was taking MMF 1,000 mg daily for 1.5 years prior to anifrolumab initiation. Three weeks after initiating monthly infusions of anifrolumab 300 mg, she presented to our dermatology clinic with hyperpigmented and erythematous macules – some polycyclic – involving the upper arms, chest, back, neck, face, and abdomen (Figure 1). KOH staining was markedly positive, and a punch biopsy of the right arm confirmed dermatophytosis. She was started on itraconazole 100 mg daily for 1 week. After 1 week of itraconazole treatment dermatophytosis recurred 2 weeks later so she was started on daily itraconazole 200 mg daily for chronic suppression of widespread tinea corporis for the following 4 months.
Patient 5 is a 28‐year‐old female with a history of SLE and DLE. Five months after anifrolumab 300 mg monthly infusion initiation, she presented to the emergency department critically ill and septic, with CT imaging showing a right psoas abscess (Figure 1). She was on no other immunosuppressive medications at this time. While in the hospital, blood cultures tested positive for Prevotella bivia, a gram‐negative anaerobic bacterium, and she was treated with piperacillin‐tazobactam. Five days after discharge, she presented again for worsening pain, fevers, and increased drain output around her psoas abscess. She was found to have a new paracolic gutter and perihepatic abscesses on CT imaging. Anifrolumab was stopped and the patient improved with antibiotics and abscess drainage.
This case series highlights three severe, atypical infections that occurred in patients on anifrolumab. Limitations of this study include its retrospective nature. Although all patients were on anifrolumab at the time of infection, we cannot confirm whether the medication truly caused the adverse event. However, as type I IFNs are a major line of host defense against viruses and other microorganisms, it is likely that type I IFN blockade via anifrolumab may have played a role. 5 Notably, most patients were on additional immunosuppressive medications, so is it likely that anifrolumab may have acted in conjunction with these medications to increase infection risk. Anifrolumab may provide great benefit for some people with SLE; however, physicians should carefully consider the benefits and risks of administration, especially in people with a history of recurrent infections or known risk factors for infection.
FUNDING
This manuscript was funded by the National Institutes of Health‐USA (NIH‐USA) grants R01AR071653 (to V P Werth), and the United States Department of Veterans Affairs Merit Review BX005921‐01 (Veterans Health Administration, Office of Research and Development and Biomedical Laboratory Research and Development, to V P Werth). Funding was also provided by the American Academy of Dermatology and Society of Investigative Dermatology (Gap Year Fellowship Program Grant, to S Chambers).
CONFLICT OF INTEREST STATEMENT
None.
ACKNOWLEDGEMENTS
Open access funding enabled and organized by Projekt DEAL.
REFERENCES
- 1. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an Anti‐Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017;69(2):376‐386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Crow MK, Ronnblom L. Type I interferons in host defence and inflammatory diseases. Lupus Sci Med. 2019;6(1):e000336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Larsen ML, Skouboe MK, Mogensen TH, et al. Dangers of Herpesvirus Infection in SLE Patients Under Anifrolumab Treatment: Case Reports and Clinical Implications. Am J Case Rep. 2024;25:25:e944505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Tummala R, Rouse T, Berglind A, Santiago L. Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers. Lupus Sci Med. 2018;5(1):e000252. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Boxx GM, Cheng G. The Roles of Type I Interferon in Bacterial Infection. Cell Host Microbe. 2016;19(6):760‐769. [DOI] [PMC free article] [PubMed] [Google Scholar]